Download Global irrational antibiotics/antibacterial drugs use: A current and

Microbial
pathogens and strategies for combating them: science, technology and education (A. Méndez-Vilas, Ed.)
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Global irrational antibiotics/antibacterial drugs use: A current and future
health and environmental consequences
Godfrey S. Bbosa1, 2 and Norah Mwebaza1
1
Department of Pharmacology and Therapeutics, Makerere University College of Health Sciences, P.O.Box 7072,
Kampala, Uganda
2
Department of Primary Care and Population Sciences, University of London, London, United Kingdom
Antibacterial/antibiotic drugs have tremendously improved the health of humans and animals since the antibiotic golden
age up to date. Currently the emergence of antibiotic/antibacterial resistance due to irrational drug use in medical and
veterinary practice, food industries, agriculture and in communities is posing a global health problem. Most of the unused
drugs, drug metabolites and residues enter the environment by various means thus affecting the natural ecosystems. They
select the antibiotic-resistant mutants and facilitate the acquisition of antibiotic resistance determinants by the genetransfer elements that are increasingly spreading among the environmental microbiota. They destroy the susceptible
microbiota such as the Cyanobacteria that is responsible for production of third of the total free oxygen and carbon
dioxide in the environment. They affect the natural metabolic processes of the microbiota by altering the structure and the
physiology of all the microorganisms in the environment and thus affecting the maintenance of the global activity of the
microbiosphere. Antibiotic/antibacterial resistance increases the cost of treatment, prolonged hospitalization due to
resistant bacterial infections in addition to some individuals getting exposed to second and third-line drugs that are highly
toxic thus increasing the adverse drug reactions in humans and economic loss in animals.
Keywords antibiotic/antibacterial resistance, irrational antibiotic use, global consequences, humans, animals, environment
1. Introduction
Antimicrobial drugs have been widely used for more than 50 years to improve both human and animal health since the
antibiotic golden age up to date [1]. The discovery of the antibiotic and antibacterial agents since 1940’s, revolutionized
the treatment of infectious bacterial diseases that used to kill millions of people during the pre-antibiotic golden age
worldwide [2, 3]. Antibiotics are chemical substances naturally produced by various species of microorganisms such as
bacteria and fungi like actinomycetes and streptomyces that kill or inhibit the growth of other microorganisms. Among
the major sources of antibiotics include Streptomyces, Penicilliums, Actinomycetes and Bacilli [3, 4]. It is estimated that
about 100,000 tons of antibiotics are produced globally [2-4]. About 80% of the antibiotics/antibacterial agents
produced are used as feed additives in livestock production as growth enhancers and for prophylactic use due to the
suppressed immune system caused by the overcrowding of the animals leading to stress [5, 6]. They are also used in
agriculture especially horticulture and tissue cultures [7] and food industries as food preservatives [8] and in
commercial ethanol production [9, 10]. In all these, the antibiotics/antibacterial drugs eventually enters the environment
and cause deleterious effects to the microbiota.
Box 1 Key definitions
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Antibiotics in strict sense are ‘‘natural chemical substances produced by microorganisms like bacteria and
fungi that destroy or inhibit the growth of other microorganisms like bacteria and fungi’’ (According to the
original definition by the Nobel laureate Selman Waksman) [4]
Antibiotics in broader sense ‘‘are selective antimicrobial agents other than disinfectants, antiseptics and
substances used solely as antineoplastics that, on application to living tissue or by systemic administration,
they kill or prevent the growth of susceptible microorganisms and also include the synthetically or semisynthetically antibacterial agents like sulfonamides and fluoroquinolones’’ [1].
Antibacterial agents are chemical substances that are either natural, semi-synthetic or synthetic that kills or
inhibits the growth of bacterial microorganisms [1].
Antimicrobial drugs are chemical substances or drugs that kill or inhibit the growth of a variety of
microorganisms like bacteria, viruses, fungi, and parasites [1].
Sub-therapeutic use or Non-therapeutic use is ‘‘any use of antibiotics/antibacterial drugs as a feed or
water additive in the absence of any clinical sign of disease in the animal for growth promotion, feed
efficiency, weight gain, routine disease prevention, or other routine purpose’’[11].
Antimicrobial resistance or Antibiotic-resistant infection is where new emerging strains of microorganism
like bacteria that have been found to survive traditional antibiotic exposure or the bacteria are no longer
susceptible to an antimicrobial drug [12].
Self-medication is the ‘‘use of drugs or pharmaceutical products by the consumer to treat self recognized
disorders or symptoms or the intermittent or continued use of the medication prescribed by the physicians
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for a chronic or recurring diseases or symptoms’’ [13].
Rational drug use is where a “Patients receive medications appropriate to their clinical needs, in doses that
meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and
their community” [14].
Irrational drug use is the opposite of Rational drug use[14].
Antibiotic misuse is sometimes called antibiotic abuse or antibiotic overuse that refers to the misuse and
overuse of antibiotics or failure to take the entire prescribed course of the antibiotic leading to serious
effects on public health [14].
2. Global use and irrational use of antibiotics/antibacterial agents’ in humans,
animals, agriculture and food industries
Antibiotics/antibacterial drugs have long been used in treatment and controlling of bacterial diseases in humans,
animals and plants [3]. In animals, they are added to feeds to enhance the growth and prevent opportunistic infections
caused by stress due to overcrowding of animals [3, 15]. In food industries, they are used as preservatives [8]. However,
in all these cases, these drugs are irrationally used contributing to the selection of the pathogenic antibiotic resistant
bacterial organisms in the environment that can spread globally thus threatening the lives of both humans and animals
[16]. They can also affect the microbiota in the ecosystem leading to the disruption of the various environmental cycling
of the organic matter.
2.1. Antibiotics/antibacterial drugs use in humans
In humans, antibiotics/antibacterial drugs are commonly prescribed, sold and used to treat bacterial diseases worldwide
in irrational manner [17]. The problem has overwhelmingly increased due to financial and budgetary constraints, market
inefficiencies, distortion and behavior of health systems, health workers and pharmaceutical companies [12]. The
complementary medicine specialists or traditional herbalist and quacks also use allopathic drugs like antibiotics to treat
all types of infections, with lack of expertise and knowledge on their use [12]. It is reported that about 1/3 to 2/3 of
primary health care patients receive twice the antibiotics than clinically needed contributing to irrational antibiotic use
[18]. Complex socioeconomic and behavioral factors have been associated with antibiotic misuse among health care
professionals, unskilled practitioners and public [19]. Poor drug quality and inadequate surveillance by the regulatory
authorities especially in poor developing countries greatly contributes to antibiotic misuse [20]. The major key
determinants of irrational antibiotic use include[21, 22]: (1) lack of knowledgeable healthcare providers, prescribers that
are not qualified, supervised or supported (2) prescribers habit and behaviors where they think that use of guidelines
delay process of prescription (3) lack of availability of medicines information such as clinical treatment guidelines,
essential drug lists, national formularies and drug bulletins (4) lack of unbiased support for continuing medical
education and supervision of the healthcare providers (5) excessive pharmaceutical promotion where some prescribers
become biased to particular drugs leading to serious consequences such as side-effects, antimicrobial resistance and
high cost of treatment to the patient (6) very short consultation time (one minute) that does not allow sufficient time to
make a proper diagnosis (7) very short patient-dispenser interaction time (seconds) that does not allow sufficient time to
explain to patients how to take their medicines (8) peer pressure, where doctors fear to be seen to be prescribing
differently from their colleagues especially senior consultants who may set inappropriate prescribing norms (9) patient
demand from prescribers to prescribe them certain drugs that are unnecessary (10) lack of diagnostic support services
such as laboratory services (11) poor infrastructure like the inability to undertake observation or follow-up of patients
(12) economic incentives where prescribers gain income from dispensing or selling the medicines they prescribe (13)
inappropriate medicines supply and appropriate ones are not provided [22]. These factors increase irrational antibiotic
use and enhance the selection of antibiotic resistant pathogenic bacterial organisms that can cause significant mortality,
morbidity and increased health-care costs[22, 23]. Serious antibiotic misuse are reported in cases of (1) viral upper
respiratory tract infections and less usage for pneumonia and (2) serious overuse of antibiotics in acute cases of diarrhea
and limited use of oral rehydration salt solution [22-25]. Access to affordable health care is limited in many low and
middle income countries hence many people rely mainly on self-medication and purchasing of antibiotics directly from
pharmacies, street vendors or markets [26]. Self-medication involves the ‘‘use of medicinal products by the consumer to
treat self recognized disorders or symptoms or the intermittent or continued use of the medication prescribed by the
physicians for a chronic or recurring diseases or symptoms’’ [27, 28]. Self medication with antibiotics or the use of
non-prescribed antibiotics including leftover antibiotics is common in both developed and developing countries, in
which the point prevalence ranges from 3% to 75% thus increasing irrational antibiotic use globally [13].
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2.2. Antibiotic/antibacterial drugs use in treatment of animals
Antibiotics/antibacterial drugs have been widely used globally in animals for more than 50 years, with tremendous
benefits in animal production and economic development [1]. Several antibiotic/antibacterial drugs are used in the
treatment of many bacterial diseases of animals’ especially in food-producing animals globally. Many of these agents
are at the same time used in bacterial infections in humans (table 1) [3, 6, 8]. However, many of these drugs are abused
by veterinarians as healthcare professionals and the general public where many farmers treat their sick animals with
antibiotics/antibacterial drugs without seeking professional consultation. The problem is worse in developing poor
countries that have privatized veterinary services making the cost of treatments to be very expensive for the farmers.
Many farmers access these agents and treat their animals even in cases where use of antibiotic/antibacterial agents
would be unnecessary. As a result of this, massive quantities of antibiotics/antibacterial drugs used, are released in the
environment thus increasing selection of the antibiotic resistant bacterial organisms that can spread from the animals to
humans especially the bacterial zoonoses, increasing the cost of treatments in both animals and humans[29-31] . The
problem is likely to increase globally leading to severe future consequences similar to the pre-antibiotic golden age
situation.
Table 1 Major classes of antibiotic/antibacterial shared by animals and humans [5, 11]
Class of antibiotic/antibacterial drugs
β-lactams – penicillins & cephalosporins
Macrolides & lincosamides
Aminoglycosides
Fluroquinolones
Tetracyclines
Sulfonamides
Fluoroquinolones
Streptogramins
Polypeptides
Phenicols
Pleuromultilin
Bambermycins
Quinoxalines
Aminocoumarins
Examples
Penicillin, amoxicillin; ceftiofur
Tylosin; tilmicosin; tulathromycin, lincomycin
Gentamicin; streptomycin, neomycin, spectinomycin
Enrofloxacin, danofloxacin
Tetracycline; oxytetracycline, chlortetracycline
Sulfacytine, Sulfisoxazole, Sulfamethizole, Sulfadiazine
Sulfamethoxazole, Sulfapyridine
Ciprofloxacin, Danofloxacin, Difloxacin, Enrofloxacin,
Marbofloxacin, Orbifloxacin
Virginiamycin
Bacitracin
Florfenicol
Tiamulin
Bambermycin (AmproliumR)
Carbadox
Novobiocin, clorobiocin and coumermycin A1
2.3. Antibiotics/antibacterial drugs use in the animal feed industry
Feed industries and farmers have been adding antibiotics to livestock feed since 1946, after it was realized that use of
these antibiotics caused animals to grow faster and put on weight in a short time [5, 11]. It is reported that more than
80% of all antibiotics produced globally are used in animals and some are used in aquaculture, prophylactically to
control bacterial diseases of the fish and other water animals [12, 29]. The antibiotics/antibacterial drugs cause a change
in physiological, nutritional and metabolic processes of the animals. They are used in [15, 32]:(1) stimulation of
intestinal synthesis of vitamins by bacteria (2) reduction in total numbers of bacteria (normal flora) in the
gastrointestinal tract hence reducing the competition between microorganisms and host animals for nutrients (3)
inhibition of harmful bacteria which may be mildly pathogenic or toxin-producing (4) inhibition of bacterial urease(5)
improved energy efficiency of the gut (6) inhibition of bacterial cholytaurin hydrolase activity (7) nutrient sparing (8)
improvement of nutrient pharmacokinetics especially absorption from the small intestinal epithelium (9) modification
of intestinal enzyme activity (10) reduced immune stimulation due to stress caused by overcrowding of the animals (11)
modification of rumen microbial metabolism [15, 32].
2.4. Antibiotic/antibacterial drugs use in food industries
Many bacterial organisms from humans, animals and the environment commonly contaminate foods and food products
in food industries and other perishable foods especially during processing and transportation to the markets in un-sterile
conditions [8]. The bacteria attack and utilize nutrients needed by humans in the foods and also cause spoilage of foods
leading to economic and financial loss. The bacterial contamination also increases the cost of de-contamination of
industrial facilities [33-36]. As a result, many antibiotic/antibacterial drugs are used irrationally in most cases to control
bacterial contaminants in food industries.
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2.4.1. Antibiotic drugs use in ethanol production
During ethanol production especially in commercial brewery plants, yeast is used to convert starch to ethanol [35-37].
However ethanol fermentation tanks occasionally become contaminated with bacteria especially “lactic acid
bacteria”[35-37]. Among the lactic acid bacteria species that have been reported to contaminate fuel ethanol
fermentations, include both Gram-positive and Gram-negative bacteria species such as Lactobacillus, Pediococcus,
Enterococcus Acetobacter, Gluconobacter, Leuconostoc, Weissella and Clostridium, with the Lactobacillus species the
most predominant contaminant [35-37]. The Lactobacillus species have the capacity to grow rapidly, tolerate ethanol
disinfection and the low pH allows these bacterial organisms to effectively compete favorably with the yeast [36, 37].
The increased and prolonged bacterial contamination drains the available sugars that can be converted to ethanol. The
bacterial organisms convert the sugars to lactic or acetic acid that lowers the quality and quantity of the ethanol
production [36, 37]. Also the bacteria scavenge essential micronutrients required for optimal yeast growth and
efficiency in ethanol production. The most commonly used antibiotics/antibacterial agents to selectively kill bacterial
contaminants and spare yeast in ethanol production include penicillin, virginiamycin, erythromycin, tylosin and
tetracycline [9, 33, 36]. The massive use of the antibiotics/antibacterial agents in commercial ethanol production
contributes to destruction of the useful bacteria (normal flora) in the hosts and in the environment as well as increased
selection of antibiotic resistant pathogenic bacteria that can spread globally in the environment to human and animals as
well as lowering the effectiveness of the antibiotics [10].
2.4.2. Antibiotics as food preservatives
Various antibiotics/ antibacterial drugs have long since 1940’s been used in the preservation of perishable foodstuffs
and food products. Among the commonly used antibiotics include chlortetracycline, oxytetracycline, chloramphenicol,
penicillic acid, penicillin and streptomycin. Also these agents are used in preservation of fish [38]. The tetracyclines are
commonly used in food industries to prevent growth of harmful bacteria in poultry product, fish, canned foods, cheese,
meat, sausages and other non-sterile animal products [39, 40]. Natamycin (pimaricin) is a polyene macrolide antibiotic
produced by submerged aerobic fermentation of Streptomyces natalensis and related species [40]. It is used in the food
industry as a "natural" preservative for dairy product like cheese and meat, wine, soft drinks like juice, convenient food
and baking food [38-40]. In developing and poor countries like Uganda, some local milk coolants commonly use
antibiotics to prevent milk spoilage by bacteria especially Lactobacillus organisms thus predisposing consumers to subtherapeutic levels of these drugs that causes selection of antibiotic resistant bacterial pathogens in humans, animals and
environment [41].
2.5. Antibiotics/antibacterial drugs use in agriculture (horticulture)
Several antibiotics/antibacterial agents are commonly used in horticulture and agronomy to control bacterial diseases.
Oxytetracycline and streptomycin have long been used in horticulture since 1950s. They are used in the control of
bacterial diseases in high-value fruits, vegetables, trees producing timber and ornamental plants [42]. In 1997, it was
reported that more than 30,800 pounds of streptomycin and 26,700 pounds of oxytetracycline were used to control
bacterial infections in fruit trees in the USA [43]. Antibiotics are widely used prophylactically in plant tissue culture and
biological research to prevent bacterial contaminants that would attack the media rich in sugars [42]. However, the use
of these drugs conflicts with the normal principles of prophylactic use, ‘‘in that the ‘pathogen’ is unknown and is of
uncertain susceptibility and the period of use of these antibiotics is prolonged’’ [44]. Oxytetracycline, is used in
treatment of bacterial spot in peach pecan trees and sometimes its combined with gentamicin . Streptomycin was the
first antibiotics used in the treatment of plant diseases since 1955 and some times combined with oxytetracycline and
oxolinic acid in the control of fire blight bacterial diseases in rosaceous plants like pears and apples [42].
Chloramphenicol is used to control bacterial leaf blight in rice [42]; polyoxins are used to control rice sheath blight and
black spot [42]; the polyene macrolides act as systemic fungicides [42]; cellocidin is used to control rice blight spot
[42]; griseofulvin used in apple blossom blight and Fusarium wilt of melon [42]; cycloheximide is used in control of
downy mildew on onions [42, 43] and blasticidin-S inhibits the growth of many Gram positive and Gram negative
bacteria and has antiviral and antifungal activity [42]. However the use of many of these agents in agronomy and
horticulture globally has become a public health importance since these drugs are also used in humans and animals to
treat bacterial diseases [31]. Their massive use promotes the selection and emergence of resistant bacterial strains in
both humans and animals that may be difficult to control.
3. Antibiotics/antibacterial drugs and the bacterial organisms in the environment
Humans and animals health have long benefited from healthy microbial population especially bacteria in the
environment. The bacterial organisms are ubiquitous in the environment and are resident in soil, water, air, deep sea
hydrothermal vents and soda lime lakes [30, 45]. They are responsible for recycling nutrients in soil and purification of
water. Humans and animals have microflora that live on and in the body where they offer first line defense mechanism
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and protection against foreign pathogens by competition [46]. Microbes have long been used for centuries to provide
humans and animals with food through microbial fermentation of sugars to produce carbon dioxide used in bread
baking, beer and wine production using yeast that convert sugars into alcohol, yogurt and cheese produced by bacterial
fermentation of lactose, the sugar found in milk [46]. Also microbes like phytoplankton serve as the nutrient source that
indirectly feeds all marine animals. Microorganisms are involved in the biodegradation of waste generated by industries
and households. They also detoxify acid amines in drainages and other toxins dumped into the soil and water. The
biodegradation of these substances releases nutrients that can be used to feed plants or algae that in turn feed all animals
and humans globally [46]. The bacterial organisms like Cyanobacteria are responsible for more than a third of total free
O2 production and CO2 fixation in the environment that is utilized by animals, humans and plants in process of
respiration and other biochemical reactions in the environment [30]. The microbes are useful in the decomposition of
dead animal and human bodies, plants as well as in waste water treatment like sewerage septic system or waste water
treatment plants where aeration microbes remove organic materials from the filthy waters before it can safely return to
the rivers, streams, lakes, seas and oceans [30, 47, 48] (figure 1). The methane produced during sewerage treatment by
bacteria can be used to generate heat or electricity. Also some microorganisms are useful in biosynthesis of various
food products by bacterial fermentation such as xanthan gum, a food thickener, vitamin B12, riboflavin, and vitamin C
and about 70% of antibiotics currently in use, are also the product of microbial fermentation [30, 46, 47]. The increased
massive antibiotic pollution in the environmental can interfere with all these processes leading to the destruction of all
forms of the ecosystem and the selection of resistant pathogenic bacteria.
Fig. 1 Sources and distribution of antibiotics/antibacterial drugs in the environment (Adopted from Kümmerer, 2003 and modified)
[49]
4. Mechanisms of spread of antibiotic resistance
Several antibiotics are natural compounds that have been in contact with environmental microbiota for millions of
years. They are biodegradable and some used as a food resource for several microorganisms [29, 49, 50]. In the
environment the bacterial organisms are exposed to sub-therapeutic concentrations of these antibiotics where some are
killed and others develop resistant mechanisms to avoid the drugs. The antibiotic resistant bacterial organisms are
selected from the several populations of bacteria in the environment mainly by horizontal gene transfer mechanisms and
then spread to both humans and animals globally causing severe bacterial diseases that contribute to high morbidity and
mortality (figure 2 and figure 3).
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Fig. 2 Schematic representation of the interactions between pollution, resistant bacteria and aquatic environments (Adopted from
Coutinho, 2013)[51]
Fig. 3 Selection of microbial resistance
Several mechanisms have evolved in bacteria which confer them with antibiotic resistance. These mechanisms can
chemically modify the antibiotics/antibacterial drugs and render them inactive. The inactivation of the
antibiotics/antibacterial agents by bacterial is achieved by the rapid physical removal of the drug from the cell, or
modifying the target site so that it is not recognized by the antibiotic and enzymatic inactivation of the antibiotics by
bacteria which is the most common mode of antibiotic resistance [52-54]. Antibiotic resistance in bacteria occur in two
ways and it may be an inherent trait of the organism in the cell wall structure that renders it naturally resistant, or it may
be acquired by means of mutation in its own DNA or acquisition of resistance from DNA of another source [52-56].
a) Intrinsic or inherent or natural resistance is where microorganisms naturally or inherently become resistant to an
antibiotic due to lack of target sites or molecules for the antibiotic, lack of transport system for an antibiotic and
therefore the drug does not affect them or they naturally have low permeability to those agents because of the
differences in the chemical nature of the drug and the microbial membrane structures especially for those that require
entry into the microbial cell in order to effect their action [52-56].
b) Acquired resistance is where several mechanisms are developed by bacteria in order to acquire resistance to
antibiotics. It occurs by either modifying the existing genetic material or the acquisition of new genetic material from
another source [52-56]. There are two major ways in which gene transfer occurs in bacteria and include [52-56]: (1)
Vertical gene transfer where there is spontaneous mutation frequency for antibiotic resistance occurring in the order of
10-8- 10-9. This is where one in every 108- 109 bacteria in an infection will develop resistance through the process of
mutation. And once resistant genes have developed, they are transferred directly to all the bacteria progeny during DNA
replication in the process of vertical gene transfer or vertical evolution. In this way, the wild type (non mutants) bacteria
are killed and the resistant mutant survives and grows. (2) Horizontal gene transfer is another mechanism beyond
spontaneous mutation that is responsible for the acquisition of antibiotic resistance. Lateral or horizontal gene transfer
(HGT) is a process in which the genetic material contained in small packets of DNA can be transferred between
individual bacteria of the same species or even between different species [52-56]. The spread of antibiotic immunity
among bacteria is an evolutionary phenomenon mediated by plasmids, transposons, and integrons that carry DNA that
encodes attack enzyme, efflux pumps, and other protective devices [52-56]. Bacterial organisms can acquire resistance
through different mechanisms such as [57, 58]: (1) Conjugation where bacteria can fuse and exchange plasmids and
sometimes chromosome fragments. The plasmids have a broad host range and are able to cross genus lines during the
gene transfer. (2) Transfection or transduction is where viruses can infect bacteria and fungi, passing along genes from
one infected organism to the next (phage). These genes sometimes encode resistance factors. The use of antibiotic
growth promoters in animal husbandry may increase the amount of free phage in the gastrointestinal tract that may
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contribute to the spread of antibiotic resistance. (3) Transformation is where a bacterium lyses in its environment such
that some of the actively-growing bacteria in that vicinity can pick up its DNA leading to antibiotic resistance that can
be spread in the bacterial population due to plasmids such as R plasmids that are more easily used by the recipient
bacterium than chromosomal materials [46, 59].
The acquired resistance genes cause the bacterium to express the various resistance mechanisms as a way to avoid
the antibiotics exposed to them. The various mechanisms of acquired resistance expressed by bacteria include [54, 58,
60-62]: (1) the presence of an enzyme that inactivates the antimicrobial agent or enzymatic alteration of the antibiotic
(2) metabolic bypass of the targeted pathway or the presence of an alternative pathway for the enzyme that is inhibited
by the antimicrobial agent (3) a mutation in the antimicrobial agent’s target, which reduces the binding of the
antimicrobial agent or drug sequestering by protein binding (4) post-transcriptional or post-translational modification of
the antimicrobial agent’s target, which reduces binding of the antimicrobial agent or modification of targets (5) reduced
uptake of the antimicrobial agent (6) active efflux of the antimicrobial agent or active pumping of drugs out of the cell
(7) overproduction of the target of the antimicrobial agent (figure 4).
Fig. 4 Mechanisms of horizontal gene transfer (HGT) in bacteria and the various antibiotic resistance strategies (Adopted from
Todar, 2011, Encyclopædia-Britannica, 2013)[60-62]
5. Current and future consequences of antibiotic/antibacterial drugs pollution in the
environment
Antibiotics/antibacterial agents are important ecological factors in the environment that could potentially affect almost
all microbial communities. The massive misuse and abuse of antibiotics leads to their accumulation in the environment
especially the quinolones that are slowly biodegradable [29, 45, 50]. In the environment, they cause deleterious effects
to the bacterial population such as phylogenetic structure alteration, resistance expansion and ecological function
disturbance in the micro-ecosystem. The ecological functional disturbances by the antibiotics in the environment
include nitrogen transformation, methanogenesis and sulfate reduction [31, 45, 49]. The accumulated antibiotic in the
biosphere affects the structure and activity of environmental microbiota leading to alteration of the ecosystem [30]. The
increased antibiotic concentrations in natural ecosystems have a significant consequence in human therapy in hospitals
and livestock production and in agriculture due to the increased selection of the antibiotic resistant pathogenic bacterial
organisms that can spread globally [30]. These changes also contribute to structural alteration of the natural microbial
populations and also alteration of the physiology of microorganisms [30]. The selection of the antibiotic-resistant
mutants favors the acquisition of antibiotic resistance determinants by gene-transfer of elements that can spread among
the environmental microbiota. The antibiotic pollution can enrich the bacterial population with intrinsically resistant
microorganisms and reduce the population of susceptible microbiota like Cyanobacteria, which are responsible for
more than a third of total free O2 production and CO2 in the environment[30]. The increased elimination of the
Cyanobacteria population due to antibiotic/antibacterial agents pollution poses a great threat to the natural environment
and the survival of all Microbiota, animals and humans and hence the maintenance of the global activity of the
microbiosphere and macrobiosphere [30, 50]. Even though a reduction in the prevalence of resistance has been reported
after discontinuation of a given antibiotic, the total restoration of bacterial population to its previous antibioticsusceptible situation is not easily achievable [52, 61]. Many emerging bacterial diseases due to increased resistant
pathogenic organisms from the environment are likely to increase in the future that would lead to a significant mortality
of both humans and animals if the trend of antibiotics/antibacterial drugs use globally is not changed, the situation may
return to the pre-antibiotic golden age.
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6. Current and future consequences of irrational antibiotic/antibacterial drugs use on
health
Since the period of golden antibiotic age and in the 1950s, there has been a steady occurrence of resistance in many
bacteria due to acquisition of the few genetic mechanisms that are transferred through vertical and horizontal antibioticresistance genes using the transfer-proficient elements such as plasmids, transposons, and integrons [51, 53, 63]. The
selection of the pathogenic resistant antibiotic bacteria has facilitated the global spread of many resistant organisms in
humans, animals and the environment and some are zoonotic bacterial infections that does not respect geographical or
biological borders [12, 39]. The lack of development of newer and effective antibiotics by the pharmaceutical
companies due to the high cost and the emergence of pathogenic resistant bacterial diseases is critical in the
management of these bacterial diseases in future especially if nothing is done to preserve the still few effective
antibiotics/ antibacterial drugs.
6.1. Implication of antibiotic resistant bacterial infections and diseases to human health
The increased emergence of pathogenic antibiotic resistant bacterial diseases causes detrimental effects to human and
the burden is likely to worsen in the future [22, 64]. Among the serious consequences due to these resistant bacterial
diseases include [14, 22, 64]: (1) reduction in the quality of antibiotics/ antibacterial drug therapy available in the
management of these resistant diseases and the situation may return to the pre- golden antibiotic age. (2) wastage of
resources especially where finances are diverted to purchase expensive drugs to manage resistant diseases may lead to
lack of vital drugs used to treat other common diseases [65]. (3) There is increased risk of unwanted side effects such as
adverse drug reactions since many of the patients with resistant bacterial diseases in most cases are put on either the
second- or third –line drugs that are expensive and toxic like in the case of multi-resistant tuberculosis. (4) There are
increased cases of treatment failures due to the resistant bacterial diseases causing prolonged hospitalization, increased
cost of treatment to the society and death. (5) High mortality caused by resistant bacterial diseases could be a serious
burden globally and it is reported that more than 25 000 people in the European Union die of antibiotic resistant
bacterial diseases annually [12] and this may have a serious consequences on healthcare systems especially in poor
nations. (6) The resistant bacterial diseases may cause a psychosocial impact, where patients believe that there is "a pill
for every illness" leading to increased demand for drugs. (7) The increased use of antibiotics especially the broad
spectrum antibiotics like tetracycline by communities may lead to the destruction of microflora making such
individuals more susceptible to fungal infections especially Candida infection [16, 66]. (8) There is a possibility of
global spread of the pathogenic resistant bacterial in both humans and animals leading to socio-economic impact and
stress among the global population.
6.2. Implication of antibiotic resistant bacterial diseases to animal health
Like in humans, bacterial diseases of animals are a burden globally and many of them are zoonotic thus making animals
as reservoirs of bacterial infections to humans. It is reported that about 75% of the total global antibiotics/antibacterial
drugs produced are used in animals as growth promoters, for chemoprophylaxis and treatment of sick animals. The
overuse and misuse of these agents leads to increased selection of resistant pathogenic bacteria that can spread among
different species of animals and to humans. The consequences of these bacterial diseases are similar to humans in
addition to the [20]: (1) poor animal production and increased death of the animals leading to increased cost of
production. (2) increased emergence and spread of resistant zoonotic bacterial diseases that can affect the human
population worldwide. (3) The countries that rely on agriculture as their source of income will be greatly affected due to
reduced animal production, quarantine and embargo on export and imports of animal products as well as the high cost
of production. (4) Many food and animal industries will be affected due to lack of raw materials. (5) Malnutrition can
be a major problem since many people especially children from poor developing countries will lack animal products as
nutrients [25].
7. Conclusion
The global use of antibiotics/antibacterial drugs have improved the health of humans and animals since the antibiotic
golden age and the economy of many countries worldwide. These agents are used in the treatment of both human and
animal bacterial diseases. They are used by livestock farmers as feed additives to enhance growth of livestock animals.
They are used in food industries as preservatives and in commercial ethanol production to prevent bacterial
contaminants of the fermentation plants. They are used in horticulture to treat plant diseases as well as in tissue cultures.
However massive use of the antibiotics/antibacterial drugs in irrational manner has affected the environmental
microbiota of the ecosystem, destruction of useful bacteria in the environment including the normal flora as well as
increasing the selection of the pathogenic antibiotic resistant bacterial organisms that have led to their spread globally.
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This has led to economic loss in animal industry and in humans; it has also caused prolonged hospitalization, adverse
drug reactions, treatment failures, increased cost of treatment, and reduced socioeconomic status of many individuals
globally. These problems are likely to increase in future unless there is an urgent instituting of control measures
involving all stakeholders on the rational use of antibiotics/antibacterial drugs globally.
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